Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation
Glucose transporter 4 (GLUT4) in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of the insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knock-out of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal fed and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced brain glucose uptake. In response to hypoglycemia, BG4KO mice had impaired glucose sensing noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in-vitro glucose sensing of glucose inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BGK4KO mice have glucose intolerance, insulin resistance, and impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.
* Co-first authors
- Received July 27, 2016.
- Accepted October 12, 2016.
- © 2016 by the American Diabetes Association.